Thursday, December 06, 2007

Genome profile in multiple sclerosis

article and editorial
Hafler DA et al. Risk alleles for multiple sclerosis identified by genomewide study. NEJM 2007; 357:851-862.Peltonen L. Old suspects found guilty-- the first genome profile of multiple sclerosis. NEJM; 2007; 357: 927-929.

Editorial comments on use of SNP's (single nucleotide polymorphisms) to define genetic diseases. The technique has localized diseases (DM, Crohn's) to unsuspected pathways, genese without a known function, or to noncoding regions of genes. Identical twins have a 30 % concordance of developing MS; dizygotic twins, 2 %, general population, 0.1 %. Since 1972, there has been an association with HLA-DRB1 gene on chromosome 6p21. Minor loci are seen on 5p, 17q, and 19q. The above study of NS Genetics Consortium supports the prediction of multiple risk alleles.

The test analyzed more than 330,000 SNP's in 931 trios (affected patient and both parents)by monitoring the overtransmission of any SNP to the affected child with transmission dysequilibrium testing. The data support the HLA locus but also 2 interesting genes, IL2RA which encodes the alpha subunit of the IL-2 receptor (also known as CD 21) on chromosome 10p15, and IL7RA which encodes the alpha subunit of the IL-7 receptor on chromosome 5p13. IL2 receptor is critical for the regulation of T Cell responses, and IL-7 for the homeostasis of the memory T cell pool and generation of the autoreactive T cells in MS. These two genes together, though explain only a small portion of the variance (0.2%) in risk of MS.

Author suggests the potential high risk alleles in large study samples should be sequenced, to encounter, probably, rare high impact alleles with critical importance for disease risk in some families or patients (analagous to BRCA1,2 testing). Author believes other genome variants should be sought, terms finding somewhat disappointing.

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